The organoid-initiating cells in mouse pancreas and liver are phenotypically and functionally similar

Abstract

Pancreatic Lgr5 expression has been associated with organoid-forming epithelial progenitor populations but the identity of the organoid-initiating epithelial cell subpopulation has remained elusive. Injury causes the emergence of an Lgr5+ organoid-forming epithelial progenitor population in the adult mouse liver and pancreas. Here, we define the origin of organoid-initiating cells from mouse pancreas and liver prior to Lgr5 activation. This clonogenic population was defined as MIC1-1C3+/CD133+/CD26− in both tissues and the frequency of organoid initiation within this population was approximately 5% in each case. The transcriptomes of these populations overlapped extensively and showed enrichment of epithelial progenitor-associated regulatory genes such as Sox9 and FoxJ1. Surprisingly, pancreatic organoid cells also had the capacity to generate hepatocyte-like cells upon transplantation to Fah-/- mice, indicating a differentiation capacity similar to hepatic organoids. Although spontaneous endocrine differentiation of pancreatic progenitors was not observed in culture, adenoviral delivery of fate-specifying factors Pdx1, Neurog3 and MafA induced insulin expression without glucagon or somatostatin. Pancreatic organoid cultures therefore preserve many key attributes of progenitor cells while allowing unlimited expansion, facilitating the study of fate determination.

Transcription factor regulation of pancreatic organogenesis, differentiation and maturation

“…Recently, the origin of the organoid-forming epithelial cells have been identified, i.e., MIC ¡ 1C3 C /CD133 C /CD26 ¡ in the adult mouse pancreas and liver. 217 MIC ¡ 1C3 C /CD133 C /CD26 cells are phenotypically similar in both organs and are rich in Sox9 and forkhead box protein J1 (FoxJ1). 217 Later, when organoids were transplanted to Fah ¡/¡ mice, hepatocyte-like cell grafts were generated in half of the recipients.…”

“…217 MIC ¡ 1C3 C /CD133 C /CD26 cells are phenotypically similar in both organs and are rich in Sox9 and forkhead box protein J1 (FoxJ1). 217 Later, when organoids were transplanted to Fah ¡/¡ mice, hepatocyte-like cell grafts were generated in half of the recipients. 217 This demonstrated a differentiation capacity similar to hepatic organoids.…”

“…217 Later, when organoids were transplanted to Fah ¡/¡ mice, hepatocyte-like cell grafts were generated in half of the recipients. 217 This demonstrated a differentiation capacity similar to hepatic organoids. Later, the adenoviral delivery of Pdx1, Ngn3 and MafA induced insulin expression.…”

“…Later, the adenoviral delivery of Pdx1, Ngn3 and MafA induced insulin expression. 217 Hence the organoid-initiating cells have the capacity to differentiate. 217 Winglesstype MMTV integration site family member 7b (Wnt7b) is expressed in the epithelium and is required for pancreatic progenitor cell growth.…”

“…217 Hence the organoid-initiating cells have the capacity to differentiate. 217 Winglesstype MMTV integration site family member 7b (Wnt7b) is expressed in the epithelium and is required for pancreatic progenitor cell growth. 218 Pancreatic ablation of Wnt7b prior to and during the secondary transition inhibited proliferation of pancreatic progenitors and prompted pancreatic hypoplasia.…”